Polyvinylpyrrolidone For The Stabilization Of A Solid Dispersion Of The Non-Crystalline Form Of Rotigotine

ABSTRACT

The present invention relates to a method for stabilizing rotigotine, the method comprising providing a solid dispersion comprising polyvinylpyrrolidone and a non-crystalline form of rotigotine, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is in a range from about 9:3.5 to about 9:6. The present invention also relates to a solid dispersion comprising a dispersing agent and a dispersed phase, said dispersed phase comprising rotigotine and polyvinylpyrrolidone, wherein the weight ratio of rotigotine to polyvinylpyrrolidone is in a range from about 9:3.5 to about 9:6, a pharmaceutical composition comprising such a solid dispersion, in particular a transdermal therapeutic system, as well as a method for the preparation thereof.

FIELD

The present invention relates to the use of polyvinylpyrrolidone for thestabilization of a solid dispersion of the non-crystalline form ofrotigotine, the use of such a stabilized solid dispersion for thepreparation of a transdermal therapeutic system and a transdermaltherapeutic system comprising such a stabilized solid dispersion as aself adhesive matrix, which is characterized by an increased long termstorage stability due to the reduced Formation of rotigotine crystals.

BACKGROUND

Rotigotine is the International Non-Proprietary Name (INN) of thecompound(−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenolhaving the structure shown below

Two crystalline forms of rotigotine are presently known: polymorphicform I and polymorphic form II (WO 2009/068520). They can bedifferentiated by their respective physicochemical parameters, i.e.differing powder X-ray diffraction spectra, Raman spectra and meltingpoints. At room temperature, the crystalline polymorphic form II is morestable than form I, which in turn is more stable than the amorphous formof rotigotine.

Rotigotine is a non-ergolinic D1/D2/D3 dopamine agonist that resemblesdopamine structurally and has a similar receptor profile but a higherreceptor affinity.

In contrast to other non-ergolinic dopamine agonists, rotigotine hassignificant D1 activity, which may contribute to a more physiologicalaction.

In contrast to ergolinic compounds, rotigotine has a very low affinityfor 5 HT₂B receptors and thus a low risk of inducing fibrosis.

Actions on non-dopaminergic receptors (such as 5-HT₁A agonism and A_(2B)antagonism) may contribute to other beneficial effects, such asantidyskinetic activity, neuroprotective activity and antidepressiveeffects.

Rotigotine is disclosed as active agent for treating patients sufferingfrom Parkinson's disease (described in WO 2002/089777), Parkinson's plussyndrome (described in WO 2005/092331), depression (described in WO2005/009424) and the restless-legs syndrome (described in WO2003/092677) as well as for the treatment or prevention of dopaminergicneuron loss (described in WO 2005/063237) and treatment of pain(PCT/EP2007/005381).

Known pharmaceutical compositions containing rotigotine comprise atransdermal therapeutic system or patch (TTS) (described inter alia inWO 99/49852), a depot form (described in WO 02/15903), an iontophoreticdevice (described in WO 2004/050083) and an intranasal formulation(described in WO 2005/063236).

To date, various TTS for the administration of amine functional drugs,such as rotigotine and many others, have been described.

WO 94/07468 discloses a TTS containing rotigotine hydrochloride asactive substance in a two-phase matrix, which is essentially formed by ahydrophobic polymer material as the continuous phase and a dispersehydrophilic phase contained therein and mainly containing the drug andhydrated silica. The silica is said to enhance the maximum possibleloading of the TTS with the hydrophilic salt. Moreover, the formulationof WO 94/07468 usually contains additional hydrophobic solvents,permeation promoting substances, dispersing agents and, in particular,an emulsifier, which is required to emulsify the aqueous solution of theactive component in the lipophilic polymer phase. A TTS prepared byusing such a system has been tested in healthy subjects and Parkinson'spatients. However, no satisfactory drug plasma levels were achieved.

Various further TTS have been described in WO 99/49852. Various furthertransdermal therapeutic systems have been described in WO 99/49852. TheTTS used in this patent application comprise a backing layer, inert withrespect to the constituents of the matrix, a self-adhesive matrix layercontaining an effective quantity of rotigotine or rotigotinehydrochloride and a protective film which is to be removed before use.The matrix system is composed of a non-aqueous polymer adhesive system,based on acrylate or silicone.

Further TTS for the delivery of rotigotine are for example disclosed inEP 1 256 339 and in WO 2004/012730. These systems utilize a mixture ofat least one high tack and at least one medium tack amine-compatiblesilicone pressure sensitive adhesive as the main adhesive components ofthe self adhesive matrix. They provide for better flux rates andsufficient rotigotine plasma levels.

Despite the existence of TTS comprising rotigotine in the prior art,there remains room for improvement in such TTS, and in processes formaking them.

Crucial pharmaceutical aspects of the TTS are the drug release profile,distribution of the drug within the patch, drug solubility in thematrix, drug and/or patch stability, adhesiveness of the patch to theskin, smooth and complete removability of the patch from the skin.

As these parameters are influencing each other it is difficult todevelop a new patch just by amending one parameter.

Recently, it has been found that the systems as described aboveunfortunately show long-term stability problems. If rotigotine crystalsare formed in the self adhesive matrix during long term storage, crystalgrowth can lead to reduced release rates of rotigotine with the riskeventually falling below the specified values.

Due to the occurrence of a new polymorphic form (form II) of the drugsubstance rotigotine crystal formation on the commercialized patches cantake place. An attempt to modify the manufacturing process resulted onlyin very limited success. These patches still require cold storage untiladministration to the skin. This results inter glia in a morecomplicated application instructions for the rotigotine patch, like thatthe cooled drug product should be taken out of the refrigerator at least1 hour before application and the adhesive on the patch has to be warmedup when the patch is applied

In general, it is well known in the art that stabilizing the amorphousstate of a drug substance in a pharmaceutical dosage form includingtransdermal systems can be very difficult, if as in the case ofrotigotine, the amorphous form is only metastable and easily convertsinto crystals. In such a case, the self adhesive matrix as a wholerepresents a metastable solid dispersion.

It is, therefore, an object of the present invention to provide a TTScomprising rotigotine which does not exhibit the above describeddrawbacks. In particular, the TTS should display an appropriate drugrelease profile combined with adequate stability and should be stable atroom temperature.

SUMMARY OF THE INVENTION

It is now surprisingly found that when used in a specific weight ratioto rotigotine, PVP is unexpectedly able to stabilize the non-crystallineform of rotigotine and prevent rotigotine from re-crystallization in asolid dispersion, such as a self adhesive matrix of a transdermaltherapeutic system, thereby imparting sufficient long term storagestability properties to the transdermal therapeutic system, preferablyat room temperature, and without negatively influencing other relevantparameters of the TTS.

Room temperature or ambient as used in the present application is to beunderstood to apply to a range from 15° C. to 25° C. In one embodimentthe room temperature is in a range from 18° C. to 22° C. and in anotherembodiment it is about 20° C.

In a first aspect, the present invention relates to the use ofpolyvinylpyrrolidone for the stabilization of a solid dispersion of thenon-crystalline form of rotigotine in a dispersing agent, wherein theweight ratio of rotigotine to polyvinylpyrrolidone ranges from about9:3.5 to about 9:6.

In one embodiment, the weight ratio of rotigotine topolyvinylpyrrolidone ranges from about 9:3.5 to about 9:4.5.

In a further embodiment, the solubility of rotigotine in the dispersingagent without a stabilizer (e.g. PVP) is below 5 wt-%.

In one embodiment, the dispersing agent comprises at least one adhesivehaving a complex viscosity between 40 and 250 MP.

In a further embodiment, the dispersing agent additionally comprises atleast one second adhesive having a complex viscosity between 1 and 10MP.

In one embodiment the complex viscosity of the dispersing agentcomprising a mixture of adhesives is between 5 and 25 MP, preferablybetween 6 and 20 MP.

In one further embodiment, the complex viscosity of the solid dispersioncomprising a mixture of adhesives as dispersing agent and rotigotine andpolyvinylpyrrolidone in the dispersed phase is between 5 and 15 MP,preferably between 6 and 15 MP.

In a further aspect, the present invention relates to a solid dispersioncomprising a mixture of adhesives as dispersing agent and rotigotine andpolyvinylpyrrolidone in the dispersed phase, wherein the soliddispersion has a peel adhesion between 3 and 16 N/50 mm at a thicknessof 50 g/m² and/or a peel adhesion between 14 and 26 N/50 mm at athickness of 150 g/m².

In still a further aspect, the present invention relates to a soliddispersion comprising a mixture of adhesives as dispersing agent androtigotine and polyvinylpyrrolidone in the dispersed phase, wherein thesolid dispersion has a static shear adhesion between 20 and 150 min.

In another embodiment, the dispersing agent comprises at least onesilicone pressure sensitive adhesive and preferably a mixture of atleast one high tack and at least one medium tack silicone pressuresensitive adhesive.

In still another embodiment, the solid dispersion contains rotigotineand the polyvinylpyrrolidone in a multitude of microreservoirs.

In one embodiment of the invention, the solid dispersion is a selfadhesive matrix of a transdermal therapeutic system.

In a further aspect, the present invention relates to a solid dispersioncomprising a dispersing agent and a dispersed phase, said dispersedphase comprising rotigotine and polyvinylpyrrolidone, wherein the weightratio of rotigotine to polyvinylpyrrolidone ranges from about 9:3.5 toabout 9:6

In an embodiment the weight ratio of rotigotine to polyvinylpyrrolidonein the solid dispersion ranges from about 9:3.5 to about 9:4.5.

In a further embodiment the solubility of rotigotine in the dispersingagent of the solid dispersion without a stabilizer (e.g. PVP) is belowabout 0.1 wt-%.

In another embodiment, the dispersing agent of the solid dispersioncomprises at least one silicone pressure sensitive adhesive. Morepreferably, it comprises a mixture of at least one high tack and atleast one medium tack silicone pressure sensitive adhesive.

In still another embodiment, the solid dispersion comprises rotigotineand polyvinylpyrrolidone in a multitude of microreservoirs.

In another aspect, the present invention relates to the use of the abovespecified solid dispersion for the preparation of a transdermaltherapeutic system, which comprises the solid dispersion as selfadhesive matrix.

In another aspect, the present invention relates to a transdermaltherapeutic system comprising the above specified solid dispersion.

In still another aspect, the present invention relates to the use of theaforementioned transdermal therapeutic systems as medicaments.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the influence of varying rotigotine to polyvinylpyrrolidoneweight ratios on the release of rotigotine from a ITS. API=activepharmaceutical ingredient (rotigotine); PVP polyvinylpyrrolidone.“Specification” is related to the product specification of the existingNeupro® Rotigotine patch.

FIG. 2 shows the physical stability of rotigotine patches containingdifferent amounts of PVP (rotigotine:PVP weight ratio of 9:2, 9:3 and9:4) after 9 month at room temperature.

FIG. 3 shows the physical stability of rotigotine patches containingdifferent amounts of PVP (rotigotine:PVP weight ratio of 9:3 and 9:4)after 15 month at room temperature.

FIG. 4 shows the physical stability of rotigotine patches containingdifferent amounts of PVP (rotigotine:PVP weight ratio of 9:3 and 9:4)after 19 month at room temperature.

DETAILED DESCRIPTION

Polyvinylpyrrolidone (PVP) is a polymer made from the monomerN-vinylpyrrolidone. It increases the cohesion of silicone adhesives. Themolecular weight of the polyvinylpyrrolidone can be in the range from2,000 to 2,500,000 Dalton (g/mol) (given as weight average), in oneembodiment in the range from 700 000 to 1,500,000, in another embodimentin the range from 1,000,000 to 1,500,000 dalton. Various grades of PVPare commercially available from e.g. BASF Aktiengesellchaft ofLudwigshafen, Germany, e.g. under the name of Kollidon. For example, thefollowing grades of Kollidons are water soluble forms of PVP: K-12 PF(molecular weight=2,000-3,000); K-17 PF (molecular weight=7,000-11,000);K-25 (molecular weight=28,000-34,000); K-30 (molecularweight=44,000-54,000); and K-90F (molecular weight=1,000,000-1,500,000).In a preferred embodiment, the molecular weight of thepolyvinylpyrrolidone is in the range from 28,000 to 1,500,000 Dalton(g/mol). Particularly preferred are the Kollidon grades K-25, K-30 andK-90F.

It is known from previous experiments that PVP reduces drug release fromtransdermal delivery systems with rotigotine across lipophilicmembranes. Surprisingly it has been found, that a variation of therotigotine/PVP weight ratio from a range of about 9:2 to about 9:6, andin one embodiment about 9:4, has only a very small effect on drug skinpermeation but a highly significant impact on physical stability of thepatch.

The present invention is based on the finding that when rotigotine andpolyvinylpyrrolidone are employed in a specific weight ratio,polyvinylpyrrolidone is able to stabilize solid dispersions of thenon-crystalline form of rotigotine by preventing rotigotine fromcrystallization.

Thus, the present invention relates in one aspect to the use ofpolyvinylpyrrolidone for the stabilization of a solid dispersion ofnon-crystalline form of rotigotine in a dispersing agent.

According to the present invention, polyvinylpyrrolidone was found tostabilize non-crystalline rotigotine in the solid dispersion state whenthe two components are used in a weight ratio of rotigotine topolyvinylpyrrolidone, which ranges from about 9:3.5 to about 9:6 and inanother embodiment from about 9:3.5 to about 9:4.5 and in still anotherembodiment is 9:4.

In another aspect, the present invention relates to a solid dispersioncomprising rotigotine and polyvinylpyrrolidone, wherein the weight ratioof rotigotine to polyvinylpyrrolidone ranges from about 9:3.5 to about9:6, in another embodiment from 9:3.5 to 9:4.5.

In a further embodiment the solid dispersion comprises rotigotine andpolyvinylpyrrolidone in a weight ratio of 9:4.

It will be appreciated by the skilled person that any multiple of theabove weight ratios will also be encompassed by the present invention.That is, the weight ratio of rotigotine to polyvinylpyrrolidone of 9:4for example also encompasses the weight ratio of 18:8 and the weightratio of rotigotine to polyvinylpyrrolidone of 9:3.5 for example alsoencompasses the weight ratio of 13.5:5.25.

The term “stabilization” as used herein means that the non-crystallineform of rotigotine in a solid dispersion is maintained due to preventingrotigotine from crystallization over a certain period of time underdefined conditions. In particular, a stabilization of at least 2 yearsunder storage at room temperature or temperatures not exceeding 25° C.is intended. This means that degree of rotigotine crystallization in thesolid dispersion should not exceed 10%, more preferably should notexceed 5% and most preferably should not exceed 2% (all percentages usedherein are by weight, unless provided otherwise), based on the initialamount of rotigotine in the solid dispersion after 24 months storage ina sealed container at room temperature.

In one embodiment the non-crystalline form of rotigotine is amorphousrotigotine.

The term “solid dispersion” as used herein refers to a metastable systemconsisting of a dispersing agent and a dispersed phase, which isimmiscible with the dispersing agent.

The dispersing agent of the solid dispersion may be any solid orsemi-solid semi-permeable silicone-based polymer or copolymer or inanother embodiment the dispersing agent is an acrylate. The dispersingagent should provide sufficient activity and stability for the soliddispersion as well as sufficient release of rotigotine.

Usually this polymer will be a pressure sensitive adhesive (PSA) or amixture of such adhesives.

In one embodiment, the dispersing agent comprises at least one adhesivehaving a complex viscosity between 40 and 250 MP (mega-poise, i.e. 1million poise; 1 P (poise) corresponds to 1 g/(cm*s) or 0.1 kg/(m*s),i.e. 0.1 Pa*s), in another embodiment between 50 and 200 MP and in stillanother embodiment between 60 and 150 MP and in a further embodiment thecomplex viscosity is between 70 and 120 MP.

It was surprisingly found that a sufficient physical long-term stabilityof the solid drug dispersion can be achieved by when the upper complexviscosity is below 250 MP and most preferably below 200 MP.

In a further embodiment, the dispersing agent comprises at least onesecond adhesive having a complex viscosity between 1 and 10 MP, inanother embodiment between 1.5 and 5 MP and in still another embodimentbetween 2 and 3 MP.

In one embodiment the complex viscosity of the mixture of adhesives isbetween 5 and 25 MP. In another embodiment the complex viscosity of themixture of adhesives is between 6 and 20 MP. In another embodiment thecomplex viscosity of the mixture of adhesives is between 7 and 15 MP andin still another embodiment between 8 and 12 MP.

In one further embodiment, the complex viscosity of the solid dispersioncomprising a mixture of adhesives as dispersing agent and rotigotine andpolyvinylpyrrolidone in the dispersed phase is between 5 and 15 MP, inanother embodiment between 6 and 15 MP, in another embodiment between 8and 15 MP and in still another embodiment between 10 and 12 MP.

Complex viscosity was determined by using a Stress Tech Rheometer(REOLOGICA Instruments AB or equivalent) being equipped with plate/platemeasurement system with d=25 mm and a temperature regulator capable toadjust the temperature between 15 and 110° C. All rheology tests weredone in the linear viscoelastic region of the test material at anoscillation frequency of 0.1 rad/s and 30° C. Depending on the complexviscosity of the respective samples, the following parameters were used:

a) adhesives having a complex viscosity between 40 and 250 MP: thicknessof the sample films: about 2 mm; strain: 5%; gap: 1.5 mm; andb) adhesives having a complex viscosity between 1 and 10 MP: thicknessof the sample films: about 3 mm; strain: 1%, gap: 2.5 mm.

In a further aspect, the present invention relates to a solid dispersioncomprising a mixture of adhesives as dispersing agent and rotigotine andpolyvinylpyrrolidone in the dispersed phase, wherein the soliddispersion has a peel adhesion at a thickness of 50 g/m² between 3 and16 N/50 mm, in another embodiment between 4.5 and 14 N/50 mm and instill another embodiment between 6 and 12 N/50 mm, and/or has a peeladhesion at a thickness of 150 g/m² between 14 and 26 N/50 mm, inanother embodiment between 16 and 24 N/50 mm, in Still anotherembodiment between 17 and 23 N/50 mm and in a further embodiment around20.1 N/50 mm.

Peel adhesion was determined by using a tensile test machine(ZWICK/ROELL Z2.5 or equivalent). Samples were mounted on a suitabletest plate made of aluminium and left for 10 min before peeling off. Thesample films had a thickness of 50 g/m² or of 150 g/m². All measurementswere done with a peel speed of 300 mm/min and a peel angle of 90° atroom temperature.

In still a further aspect, the present invention relates to a soliddispersion comprising a mixture of adhesives as dispersing agent androtigotine and polyvinylpyrrolidone in the dispersed phase, wherein thesolid dispersion has a static shear adhesion between 20 and 150 min, inanother embodiment between 25 and 100 min, in still another embodimentbetween 30 and 80 min. and in a further embodiment the static shearadhesion is between 40 and 60 min.

Static shear adhesion was determined using a method based on DINstandard method EN 1943:2003-01 “Adhesive tapes, measurement of theshear force under static load”. In brief, for the determination of theshear force, a defined area (12 mm×12 mm) of a sample film, was stuck ona test plate made of V2A steel and is rolled twice with constantpressure (roll: m 5 kg, width=2.5 cm) in longitudinal direction for ca.1 sec. Afterwards, the test plate was vertically arranged and a standardweight (1000±5 g) was attached at the free end of the sample. The timeuntil failure of the adhesive sealing of the sample, i.e. the time untilthe weight drops down, was measured. All measurements were done at 23±2°C. and 50±5% RH. Before, the samples were allowed to equilibrate underthese standard conditions for at least 24 h.

The adhesives used in the present invention should preferably bepharmaceutically acceptable in a sense that they are biocompatible,non-sensitising and non-irritating to the skin of the recipient.Particularly advantageous adhesives for use in the present inventionshould further meet the following requirements:

1. retained adhesive and co-adhesive properties in the presence ofmoisture or perspiration, under normal temperature variations; and

2. good compatibility with rotigotine, as well as with the furtherexcipients.

Although different types of pressure sensitive adhesives may be used inthe present invention, it is preferred to use lipophilic adhesiveshaving both low drug and low water absorption capacity. Preferably, theadhesives have solubility parameters which are lower than those ofrotigotine. Such preferred pressure sensitive adhesives areamine-compatible silicone type pressure sensitive adhesives.

In a preferred embodiment the dispersing agent comprises at least onesilicone pressure sensitive adhesive and preferably a mixture of atleast one high tack and at least one medium tack silicone pressuresensitive adhesive.

Especially preferred pressure sensitive adhesives are of the typeforming a soluble polycondensed polydimethylsiloxane (PDMS)/resinnetwork, wherein the hydroxy groups are capped with e.g. trimethylsilyl(TMS) groups. Preferred adhesives of this kind are the BIO-PSA siliconepressure sensitive adhesives manufactured by Dow Corning, particularlythe Q7-4201 and Q7-4301 qualities.

However, other silicone adhesives may also be used.

Tack has been defined as the property that enables an adhesive to form abond with the surface of another material upon brief contact under lightpressure (see e.g. “Pressure Sensitive Tack of Adhesives Using aninverted Probe Machine”, ASTM D2979-71 (1982); H. F. Hammond in D. Satas“Handbook of Pressure Sensitive Adhesive Technology” (1989), 2nd ed.,Chapter 4, Van Nostrand Reinhold, New York, page 38).

Medium tack of a silicone pressure sensitive adhesive indicates that theimmediate bond to the surface of another material is weaker compared toa high tack silicone adhesive.

The mean resin/polymer ratio is approx. 60/40 for medium tack adhesives,whereas it is approx. 55145 for high tack adhesives. It is known to theskilled person that both tape and rheological properties aresignificantly influenced by the resin/polymer ratio (K. L. Ulman and R.P. Sweet “The Correlation of Tape Properties and Rheology” (1998),Information Brochure, Dow Corning Corp., USA).

Blends comprising a high tack and a medium tack silicone type pressuresensitive adhesive comprising polysiloxane with a resin are advantageousin that they provide for the optimum balance between good adhesion andlittle cold flux. Excessive cold flux may be disadvantageous since itresults in too soft solid dispersions.

Preferably, the weight ratio of a high tack to a medium tack siliconetype pressure sensitive adhesive in these blends is 1:1. However, thisdoes not exclude employing any other weight ratio.

A mixture of the aforementioned Q7-4201 (medium tack) and Q7-4301 (hightack) qualities proved to be especially useful for the preparation of asolid dispersion according to the present invention.

The solid or semi-solid semi-permeable polymer forming the dispersingagent has to satisfy the following requirements:

1. Sufficient solubility and permeability for the free base form ofrotigotine.

2. Impermeability for the protonated form of rotigotine.

In one embodiment the solubility of rotigotine (without stabilizer) inthe dispersing agent is about 5 wt-% or below and in another embodimentabout 3 wt-% or below. In still another embodiment the solubility ofrotigotine (without stabilizer) in the dispersing agent is about 2 wt-%or below and in another embodiment it is about 0.1 wt-% or below.

The dispersed phase of the solid dispersion comprises rotigotine innon-crystalline form and a stabilizer, for example polyvinylpyrrolidone,and optionally further pharmaceutically acceptable excipients, such aspermeation enhancers and antioxidants. In one embodiment the stabilizeris selected from polyvinylpyrrolidone and in a preferred embodiment fromwater soluble polyvinylpyrrolidone. Copolymers of polyvinylpyrrolidoneand vinyl acetate, polyethyleneglycol, polypropyleneglycol, glycerol andfatty acid esters of glycerol or copolymers of ethylene and vinylacetatemight also be considered for such use.

Suitable permeation enhancers may be selected from the group of fattyalcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol orits fatty acid esters, N-methylpyrrolidone, terpenes such as limonene,[alpha]-pinene, [alpha]-terpineol, carvone, carveol, limonene oxide,pinene oxide, 1,8-eucalyptol and most preferably ascorbyl palmitate.

Suitable antioxidants are sodium metabisulfite, ascorbylpalmitate andDL-alpha tocopherol.

Unless expressly indicated otherwise, any references to rotigotine inthe context of this invention and the claims of this application meanrotigotine in the form of its free base. In some cases, however, tracesof rotigotine hydrochloride may be contained in a rotigotine preparationbut these traces typically do not exceed 5 wt-%, based on the amount ofthe free base. More preferably the content of hydrochloride impuritiesshould be less than 2 wt-%, even more preferably less than 1 wt-% andmost preferably the rotigotine used in the present invention containsless than 0.1 wt-% or no hydrochloride impurities at all.

A further step, which may be taken for reducing the amount of the saltform of rotigotine, is isolating the free base form of rotigotine insolid form prior to the preparation of the solid dispersion. If the freebase of rotigotine is produced in situ during the manufacture of thesolid dispersion by neutralizing an acid addition salt, a certainresidue of the ionized drug form will remain (usually >5 wt-% and up toapproximately 10 wt-%). Therefore, such in situ preparation of the freebase form will generally not be suitable for practising the presentinvention.

It will be understood by a person skilled in the art that rotigotineexists in various isomeric forms. It thus has also to be understood thatany single isomer or a mixture of different isomers may be used in thepresent invention.

Hence, the S- or R-enantiomer or the racemate or any other enantiomericmixture of rotigotine may be used.

In one embodiment of the invention the water content of the soliddispersion is less than 0.4 wt-% and in another embodiment it less than0.2 wt-% related to the total patch matrix.

In one embodiment, high molecular weight polyvinylpyrrolidone (PVP)having a molecular weight of about 1 Mio Da is employed in the presentinvention. Rotigotine mixtures with these high molecular weight povidonegrades result in a high degree of drug immobilization at roomtemperature. However the glass temperature of mixtures of rotigotine/PVPwith a weight ratio in the range of about 9:3.5 to 9:6 is low enough toenable sufficiently high drug release at skin temperature. In oneembodiment this range is 9:3.5 to 9:4.5 and in another the weight ratiois about 9:4.

While not wishing to be bound by theory it is believed that freerotigotine is molecularly dispersed in the dispersing agent (outerphase) and that a non crystalline form of rotigotine is reversiblyassociated with PVP by forming an inner phase or microreservoir. In oneembodiment the non-crystalline form of rotigotine is amorphousrotigotine. One advantage of a stable solid drug dispersion is that itcan significantly reduce constraints often caused by low drug solubilityin polymers suitable for transdermal delivery.

This does not exclude and will normally even imply that a certainfraction of rotigotine is dissolved in the dispersing agent of the soliddispersion at its saturation concentration.

The term “microreservoirs” as used herein is meant to be understood asparticulate, spatially and functionally separate compartments consistingof a mixture of rotigotine and polyvinylpyrrolidone, which are dispersedin the dispersing agent of the solid dispersion. In one embodiment thesolid dispersion contains 10³ to 10⁹ microreservoirs per cm² of itssurface, in another embodiment this in the range of 10⁶ to 10⁹microreservoirs per cm².

The maximum diameter of the microreservoirs is less than the thicknessof the solid dispersion, preferably up to 85% of the thickness of thesolid dispersion, particularly preferably 5 to 74% of the thickness ofthe solid dispersion. For an exemplary thickness of the solid dispersionof 50 μm this corresponds to a maximum diameter of the microreservoirsin the range of preferably up to approx 40 to 45 μm.

The term “maximum diameter” as used herein is meant to be understood asthe diameter of the microreservoirs in one dimension (x-, y-, orz-dimension), which is the largest. It is clear to the skilled personthat in case of spherical diameters the maximum diameter corresponds tothe microreservoir's diameter. However, in the case of microreservoirs,which are not shaped in the form of spheres, i.e. of different geometricforms-, the x-, y- and z-dimensions may vary greatly.

In a particularly preferred embodiment of the invention, the meandiameter of the rotigotine containing microreservoirs distributed in thesolid dispersion is in the range of 1 to 40%, even more preferably 1 to20%, of the thickness of the solid dispersion. For an exemplarythickness of the solid dispersion of 50 μm this corresponds to a meandiameter of the microreservoirs in the range of preferably 0.5 to 20 μm.

The term “mean diameter” as used herein is defined as the mean value ofthe x, y, z-average diameters of all microreservoirs. The targetparticle size can be adjusted by the solids content and the viscosity ofthe solid dispersion.

The maximum and mean diameters of the microreservoirs as well as thenumber of microreservoirs per surface area of the solid dispersion canbe determined as follows: The surface of the solid dispersion isexamined with a light microscope (Leica microscope type DM/RBE equippedwith a camera type Basler A 113C). The measurement is performed byincidental polarized light analysis using a microscope at 200×magnification. A picture analysis is performed using the software NikonLuciaDi, Version 4.21, resulting in mean and maximum diameters for eachsample.

In particular preferred embodiment, the solid dispersion represents aself adhesive matrix, such as a self adhesive matrix of a transdermaltherapeutic system.

Thus, in a further aspect, the present invention relates to the use of asolid dispersion as specified above for the preparation of a transdermaltherapeutic system, which comprises the solid dispersion as selfadhesive matrix.

In another aspect, the present invention relates to a transdermaltherapeutic system comprising a solid dispersion as specified above asself adhesive matrix.

The term “transdermal therapeutic system” (TTS) as used herein refers toa matrix-type patch having a continuous self adhesive matrix in at leastits center portion, which matrix is formed by the above specified soliddispersion. Such a patch consists of a backing layer, the self adhesivematrix and a protective foil or sheet, which is removed before use.

The backing layer is inert to the components of the self adhesivematrix. It is a film being impermeable to rotigotine. Such a film mayconsist of polyester, polyamide, polyethylene, polypropylene,polyurethane, polyvinyl chloride or a combination of the aforementionedmaterials. These films may or may not be coated with an aluminum film orwith aluminum vapour. The thickness of the backing layer may be between10 and 100 μm, preferably between 15 and 40 μm.

The self adhesive matrix layer formed by the above specified soliddispersion may have a coating weight between 50 and 150 g/m², preferablybetween 50 and 75 g/m² and most preferably is 50 g/m² 5%.

Sporadically few tiny spots or bubbles may be observed in the adhesivematrix of some patches. They are small areas where the backing film canbe seen through a small hole in the adhesive matrix, and thus arereferred to as “matrix-free spots”. In general these spots do not occurand their occurrence does, moreover, not have any impact on thepharmaceutical quality of these patches.

In a particular preferred embodiment, the self-adhesive matrix is freeof particles, which can absorb salts of rotigotine on the TTS/skininterface. Examples of particles, which can absorb salts of rotigotineon the TTS/skin interface, include silica. Such particles, which canadsorb salts of rotigotine, may represent diffusion barriers for thefree base form of the drug and may result in the formation of channelsinducing some permeability of the self-adhesive matrix for theprotonated form of rotigotine, which is disadvantageous.

Preferably, the TTS contains less than 1 wt-% of inorganic silicates,most preferably it is completely free from inorganic silicates.

The protective foil or sheet will be removed immediately prior to use,i.e. immediately before the TTS will be brought into contact with thepatient's skin. The protective foil or sheet may consist of polyester,polyethylene or polypropylene, which may or may not be coated withaluminum film or aluminum vapour or fluoropolymers. Typically, thethickness of such a protective foil or sheet ranges between 50 and 150μm.

So as to facilitate removal of the protective foil or sheet when wishingto apply the TTS, the protective foil or sheet may comprise separateprotective foils or sheets having overlapping edges, similar to the kindused with the majority of conventional plasters.

In one embodiment, the TTS has a basal surface area of 0.5 to 50 cm²,and another one of about 1 to 50 cm² and in still another one of about 5to 50 cm². In another embodiment the TTS has a basal surface area of 10to 40 cm², and in another one of about 10 to 30 cm² and in another oneof about 20 to 30 cm². It goes without saying that a device having asurface area of, say, 20 cm² is pharmacologically equivalent to and maybe exchanged by two 10 cm² devices or four 5 cm² devices having the samedrug content per cm². Thus, the surface areas as indicated herein shouldbe understood to refer to the total surface of all devicessimultaneously administered to a patient.

Providing and applying one or several TTS has the pharmacologicaladvantage over oral therapy that the attending physician can titrate theoptimum dose for the individual patient relatively quickly andaccurately, e.g. by simply increasing the number or size of devicesgiven to the patient. Thus, the optimum individual dosage can often bedetermined after a time period of only about 3 weeks with low sideeffects.

A preferred content of rotigotine in the TTS is in the range of 0.1 to3.15 mg/cm². Still more preferred are 0.4 to 1.5 mg/cm² and 0.2 to 1.0mg/cm². If a 7 day patch is desired, higher drug contents will generallybe required. A rotigotine content in the range of about 0.4 to 0.5mg/cm² has been found to be particularly advantageous in that itprovides the optimum usage of the drug contained in a once-a-day TTS,i.e. there is only very little residual drug content in the TTS afteradministration. In a particular preferred embodiment, the rotigotinecontent is 0.45 mg/cm². The apparent dose administered in 24 hours byusing such a TTS usually is 40 to 50% and may be intraindividually ashigh as 80-90% of the drug amount originally contained in the ITS. Ingeneral the content of rotigotine in the TTS can be adapted accordinglyin order to provide a suitable flux for a multiple day TTS.

The TTS may be prepared by a manufacturing process, which comprisespreparing a rotigotine comprising solid dispersion, i.e. the selfadhesive matrix, coating, drying or cooling and laminating to get thebulk product, converting the laminate into patch units via cutting, andpackaging.

After preparation, the rotigotine-comprising solid dispersion containsrotigotine to a little extent in dissolved form and mainly in amorphousform. However, for preparing the solid dispersion either of the twocrystalline forms of rotigotine, i.e. polymorphic form I or polymorphicform II, may be employed as a starting material. The manufacturingprocess is described in more detail below.

The water content in the TTS obtained after preparation is in generallow enough so that no evaporation of water during preparation of the TTSis necessary. Typically, the water content in a freshly prepared patchis below 2 wt-%, in another embodiment more preferably 1 wt-% or lowerand in another embodiment 0.6 wt-% or lower, depending on the drug/PVPweight ratio.

In a particularly preferred embodiment, the ITS is a silicone-basedtransdermal therapeutic system comprising a mixture of at least one hightack and at least one medium tack amine-compatible silicone pressuresensitive adhesive as the main adhesive components, about 0.1 to 3.15mg/cm² of rotigotine in the free base form as active ingredient, andpolyvinylpyrrolidone, wherein the weight ratio of rotigotine topolyvinylpyrrolidone ranges from 9:3.5 to 9:6.

In a preferred embodiment rotigotine and polyvinylpyrrolidone arecontained in said silicone-based transdermal therapeutic system in amultitude of microreservoirs.

In still another aspect, the present invention relates to the use of theaforementioned transdermal therapeutic systems as a medicament.

In a preferred embodiment, the medicament is used in the treatment ofdiseases susceptible to the action of dopamine receptor agonists, suchas rotigotine.

Diseases, which may be treated include Parkinson's disease, Parkinson'splus syndrome, depression, the restless-legs syndrome and pain.

Also, the medicament may be used in the treatment or prevention ofdopaminergic neurone loss.

It should be understood that the term “treatment” in the context of thisapplication is meant to designate a treatment or an alleviation of thesymptoms. The treatment may be of a therapeutic or prophylactic nature.

The invention and the best mode for carrying it out will be explained inmore detail in the following non-limiting examples.

EXAMPLES Example 1: Influence of the Rotigotine to PVP Weight Ratio onthe Crystallization of Rotigotine in a TTS Sample Preparation

Samples for testing the stabilizing properties of several rotigotine topolyvinylpyrrolidone weight ratios in terms of the present inventionwere manufactured basically following the process below.

5 g Sodium metabisulfite were dispensed in 45 g water while stirringuntil a clear 10% w/w/aqueous solution is obtained.

PVP Solution

Polyvinyl pyrrolidone (Kollidon 90 F) (5 g) was added to 14.8 ganhydrous ethanol while stirring and leave the solution for swelling.After swelling the mixture is stirred until the polyvinyl pyrrolidone isentirely dissolved. After the complete dissolution of the polyvinylpyrrolidone, an aqueous 10% w/w sodium metabisulfite solution (0.022 g),0.05 g ascorbyl palmitate and 0.124 g all-rac-α-tocopherol are added.The mixture is stirred until a clear ethanolic PVP solution is obtained.

PVP-Rotigotine-Solution

An ethanolic PVP solution as described above (15.998 g) are dissolved inanhydrous ethanol (42.33 g) and the mixture is heated to 30-40° C. whilestirring. Then(−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]1-naphthalenol(rotigotine, 18 g, polymorphic form I) was added to this solution. Themixture is stirred and heated to 50-60° C.

105.75 g of an amine resistant high tack silicone adhesive (BIO-PSA®Q7-4301 mfd. by Dow Corning) (70 wt-% solution in heptane), 105.72 g ofan amine resistant medium tack silicone adhesive (BIO-PSA® Q7-4201 mfd.by Dow Corning) (70 wt-% solution in heptane), 63.54 g of thePVP-rotigotine-solution obtained above were mixed and all componentswere stirred until a homogenous dispersion was obtained.

The dispersion was coated onto a suitable fluoropolymer coated polyesterrelease liner (e.g. SCOTCHPAK® 9744) with a suitable doctor knife andthe solvents were continuously removed in a drying oven at temperaturesup to 80° C. for about 30 min to obtain a drug-containing adhesivematrix of 50 g/m² coating weight. The dried matrix film was laminatedwith a polyester-type backing foil (e.g. Hostaphan Minn. 19). Theindividual patches were punched out of the complete laminate in thedesired sizes (e.g. 10 cm², 20 cm², 30 cm²) and sealed into pouchesunder the flow of nitrogen.

Table 1 shows the composition in mg/20 cm² of the thus obtainedrotigotine patch, which comprises rotigotine and polyvinylpyrrolidone ina weight ratio of 9:2 (comparative example)

TABLE 1 Composition in mg/20 cm² of rotigotine patch 9:2 ComponentAmount (mg) Rotigotine Base 9.00 Polyvinylpyrrolidone 2.00 SiliconeBIO-PSA ® Q7-4301 44.47 Silicone BIO-PSA ® Q7-4201 44.46 Ascorbylpalmitate 0.02 DL-alpha Tocopherol 0.05 Sodium metabisulfite 0.0006Matrix coating weight 50 g/m²

The above manufacturing process was adapted to the varying amounts ofpolyvinylpyrrolidone and the slightly increased coating weight of sampleNos. 1-8 (cf. Table 2 below).

The rotigotine to polyvinylpyrrolidone weight ratio of 9:2 of sample No.1 corresponds to the rotigotine to polyvinylpyrrolidone weight ratio ofNeupro®.

During manufacturing of sample No. 2 and sample No. 3 disintegrationtendencies of the suspension were observed during the coating process.That is, compositions based on rotigotine to polyvinylpyrrolidone weightratios of 9:1 and 9:1.6 were not processable.

The 9:11 formulation of sample No. 8 was only processable under heatingduring mixing the rotigotine/PVP solution with the adhesives and coatingdue to the high viscosity resulting from the high amount of PVP.

Based on the rotigotine to polyvinylpyrrolidone weight ratio of 9:4 ofsample 5, the above manufacturing process was further adapted to areduced content of rotigotine and polyvinylpyrrolidone as well as anamended ratio of the used silicone adhesives and an increased matrixcoating weight (sample 9):

5.000 kg polyvinylpyrrolidone (Kollidon F 90) were dissolved in 33.81 kganhydrous ethanol and the obtained solution was mixed with 0.0238 kg ofan aqueous sodium bisulfite solution (10% w/w), 0.0367 kg ascorbylpalmitate and 0.09291 kg DL-α-tocopherol.

18.033 kg of the thus obtained solution were heated to 30-40° C. whilestirring and 5.199 kg crystalline rotigotine free base (polymorphic formII) were added to this solution in several portions. The mixture wasstirred and further heated up to 50-60° C. for approximately 1-2 hoursto completely dissolve the drug.

18.764 kg of the ethanolic drug/polyvinylpyrrolidone solution were addedto a mixture of 60.83 kg BIO-PSA Q7 4301 (70 wt-% solution in heptane)and 30.41 kg BIO-PSA Q7 4201 (70 wt-% solution in heptane) and it wasstirred for at least 1 hour until a homogenous dispersion was obtained.

The dispersion was coated onto a fluoropolymer coated release liner andthe solvents were continuously removed in a drying oven at temperaturesranging from 40° C. up to 115° C. to obtain a dry drug-containingadhesive matrix of 75 g/m² coating weight. The dried matrix film waslaminated with a polyester-type backing foil being siliconized on theinner side and aluminium vapor coated on the opposite side. Theindividual patches were punched out of the complete laminate and weresealed into pouches under nitrogen flow.

TABLE 2 Rotigotine to polyvinylpyrrolidone weight ratios and coatingweights of sample Nos. 1-9 Sample No. 1 2 3 4 5 6 6 8 9 Rotigotine:PVP9:2 9:1 9:1.6 9:3 9:4 9:6 9:8 9:11 9:4 [weight ratio] Coating weight 6062 62 61 59 63 61 63 75 [g/m²]

Analytical Methods

Drug release was determined using Apparatus 5 (Paddle Over Disk) asdescribed in the United States Pharmacopeia (USP 31-NF 26), Chapter 724“Drug Release”. United States Pharmacopeia Convention, Inc.: Rockville,Md., 2008 using the following conditions: dissolution medium: 900 mlphosphate buffer 4.5; temperature adjusted to 32±0.5° C.; paddlerotation speed: 50 rpm; sampling times: 0.25, 0.5, 1, 2 and 3 h,respectively.

The released drug amounts were determined by a validated RP HPLC-methodat a detection wave length of 272 nm.

Stability testing was performed with one patch of each sample. The testswere performed from 0 weeks up to 8 weeks for samples 1 to 9 and up to24 months for further patch samples of a rotigotine:PVP weight ratio of9:2, 9:3 and 9:4 after the production date under open storage conditionsof 25° C./60 RH and the occurrence of crystals was recorded by takingmicroscopic pictures. These results were confirmed by DSC for selectedsamples.

Analytical Results

Results from drug release testing of samples 1-8 are shown in FIG. 1.

Only sample Nos. 1, 5 and 6 meet the specifications set for drug releaseof the marketed Neupro® patch having a comparable matrix thickness. Invitro drug release of sample 9 (not shown) having a reduced content ofrotigotine and polyvinylpyrrolidone and an increased matrix thicknessalso meets the Neupro® specification after 3 hours, i.e. the endpoint ofthe test. For all remaining samples, the amount of rotigotine, which isreleased from the respective TTS during release testing is less than thespecified lower limit.

Results from microscopic inspection of sample Nos. 1-9 are shown inTable 3.

For the rotigotine to polyvinylpyrrolidone weight ratios of 9:1 and9:1.6 undissolved rotigotine crystals could microscopically bedetermined already in the freshly manufactured product. This findingcould be confirmed by DSC measurements and reflects the problemsoccurring during manufacturing described above for these samples.

Starting with the first week crystals were observed for the rotigotineto polyvinylpyrrolidone weight ratios of 9:2 and 9:3.

FIGS. 2 to 4 show that during long term stability testing of patchescomprising different ratios of rotigotine to polyvinylpyrrolidone atroom temperature an increasing amount of crystals was observed for therotigotine to polyvinylpyrrolidone weight ratios of 9:2 and 9:3, whereasno crystal formation was observed for the rotigotine topolyvinylpyrrolidone weight ratio of 9:4 (sample 5).

During long term testing of patches with a rotigotine topolyvinylpyrrolidone weight ratio of 9:4 (sample 5) for up to 24 monthsat room temperature no crystals were observed.

Also sample 9 with a rotigotine to polyvinylpyrrolidone weight ratio of9:4 and having a reduced content of rotigotine and polyvinylpyrrolidoneand an increased matrix thickness did not show any crystallizationphenomena after long-term storage for up 18 months at 25° C.

An increasing PVP content delayed crystal appearance as it is shown forthe rotigotine to polyvinylpyrrolidone weight ratios of 9:4 up to 9:11.

TABLE 3 Results from storage stability testing of sample Nos. 1-9 at 25°C./60% RH (+ = crystals, − = no crystals) Sample No. 1 2 3 4 5 6 7 8 9Rotigotine:PVP 9:1 9:1.6 9:2 9:3 9:4 9:6 9:8 9:11 9:4 [weight ratio] 0weeks + + − − − − − − − 1 week + + + + − − − − − 4 weeks + + + + − − − −− 8 weeks + + + + − − − − −

That is, taking also the above discussed data from release testing intoaccount, optimum results could be achieved with rotigotine topolyvinylpyrrolidone weight ratios between 9:4 and 9:6. Higher ratiosfailed to sufficiently prevent rotigotine from crystallization and madethe system prone to crystal growth or were even unprocessable. Lowerratios led to insufficient drug release by reducing the amount ofrotigotine, which is released from the patch, below those valuesspecified for the marketed Neupro® patch.

1. A method for stabilizing rotigotine, the method comprising providinga solid dispersion comprising polyvinylpyrrolidone and a non-crystallineform of rotigotine free base, wherein the weight ratio of rotigotinefree base to polyvinylpyrrolidone is about 9:6.
 2. (canceled)
 3. A soliddispersion comprising a dispersing agent and a dispersed phase, saiddispersed phase comprising rotigotine free base andpolyvinylpyrrolidone, wherein the weight ratio of rotigotine free baseto polyvinylpyrrolidone is about 9:6.
 4. (canceled)
 5. The soliddispersion of claim 3, wherein the solubility of rotigotine free base inthe dispersing agent is below 1 wt-%.
 6. The solid dispersion of claim3, wherein the dispersing agent comprises at least one silicone pressuresensitive adhesive.
 7. The solid dispersion of claim 3, wherein thedispersing agent comprises a mixture of a first silicone pressuresensitive adhesive and a second silicone pressure sensitive adhesive andwherein the solid dispersion has a complex viscosity between 5 and 15MP.
 8. The solid dispersion of claim 3, wherein rotigotine free base andpolyvinylpyrrolidone are in a multitude of microreservoirs.
 9. Apharmaceutical composition comprising a solid dispersion according toclaim
 3. 10. A transdermal therapeutic system comprising at least oneamine-compatible silicone pressure sensitive adhesive, about 0.1 toabout 3.15 mg/cm² of rotigotine free base, and polyvinylpyrrolidone,wherein the weight ratio of rotigotine free base to polyvinylpyrrolidoneis about 9:6.
 11. The transdermal therapeutic system of claim 10,wherein rotigotine free base and polyvinylpyrrolidone are contained in amultitude of microreservoirs.
 12. A transdermal therapeutic systemcomprising a solid dispersion of claim
 3. 13. The transdermaltherapeutic system of claim 12, comprising 0.1 to about 3.15 mg/cm² ofrotigotine free base and wherein the weight ratio of rotigotine freebase to polyvinylpyrrolidone is 9:46.
 14. A method for preparing atransdermal therapeutic system, the method comprising preparing a soliddispersion comprising a dispersing agent and a dispersed phase, saiddispersed phase comprising rotigotine free base andpolyvinylpyrrolidone, wherein the weight ratio of rotigotine free baseto polyvinylpyrrolidone is about 9:6.
 15. The method of claim 1, whereinthe solid dispersion further comprises a dispersing agent.
 16. Themethod of claim 15, wherein the dispersing agent comprises at least afirst adhesive having a complex viscosity between 40 and 250 MP.
 17. Themethod of claim 16, wherein the dispersing agent comprises at least asecond adhesive having a complex viscosity between 1 and 10 MP.
 18. Themethod of claim 17, wherein the dispersing agent has a complex viscositybetween 5 and 25 MP.
 19. The method of claim 15, wherein the dispersingagent comprises at least a first adhesive and a second adhesive and thesolid dispersion has a complex viscosity between 5 and 15 MP.
 20. Themethod of claim 15, wherein the dispersing agent comprises at least afirst adhesive and a second adhesive and the solid dispersion has a peeladhesion between 3 and 16 N/50 mm at a thickness of 50 g/m² and/or apeel adhesion between 14 and 26 N/50 mm at a thickness of 150 g/m². 21.The method of claim 15, wherein the dispersing agent comprises at leasta first adhesive and a second adhesive and the solid dispersion has astatic shear adhesion between 20 and 150 min.
 22. The solid dispersionof claim 3, wherein the dispersing agent comprises at least a firstadhesive having a complex viscosity between 40 and 250 MP.
 23. The soliddispersion of claim 3, wherein the dispersing agent comprises at least asecond adhesive having a complex viscosity between 1 and 10 MP.
 24. Thesolid dispersion of claim 23, wherein the dispersing agent has a complexviscosity between 5 and 25 MP.
 25. The solid dispersion of claim 3,wherein the dispersing agent comprises at least a first adhesive and asecond adhesive and the solid dispersion has a complex viscosity between5 and 15 MP.
 26. The solid dispersion of claim 3, wherein the dispersingagent comprises at least a first adhesive and a second adhesive and thesolid dispersion has a peel adhesion between 3 and 16 N/50 mm at athickness of 50 g/m² and/or a peel adhesion between 14 and 26 N/50 mm ata thickness of 150 g/m².
 27. The solid dispersion of claim 3, whereinthe dispersing agent comprises at least a first adhesive and a secondadhesive and the solid dispersion has a static shear adhesion between 20and 150 min.